The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

B cell regulation of the anti-tumor response and role in carcinogenesis

The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-β, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses. Multiple murine tumor models exhibit decreased tumor growth in B cell deficient or B cell depleted mice. In several of these models, B cells inhibit T cell mediated tumor immunity and/or facilitate conversion of T cells to CD4(+)CD25(+)FoxP3(+) T regs, which act to attenuate the innate and/or adaptive antitumor immune response. Mechanisms of suppression include the acquisition of inhibitory ligand expression, and phosphorylation of Stat3, and induction of IL-10 and TGF-β, resulting in a Breg phenotype. Breg suppressive activity may affect diverse cell subtypes, including T effector cells, NK cells, myeloid derived suppressor cells (MDSC) and/or tumor associated macrophages. B cells may also directly promote tumorigenesis through recruitment of inflammatory cells, and upregulation of pro-angiogenic genes and pro-metastatic collagenases. Breg infiltration has now been identified in a variety of solid tumor malignancies including but not limited to ovarian, gastric, non-small cell lung cancer, pancreatic, esophageal, head and neck, and hepatocellular carcinomas. Increasing evidence suggests that recruitment of B cells and acquisition of suppressive activity within the tumor bed may be an important mechanism through which B cells may modulate innate and/or adaptive anti-tumor immunity. B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response

Genome-wide association studies of cancer: current insights and future perspectives.

Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS

Behavioral and electrophysiological evidence of enhanced performance monitoring in meditators

Performance monitoring—the ability to monitor ongoing performance to detect and correct errors—is a core component of cognitive control. Impairments in performance monitoring have been associated with several psychiatric disorders, including attention deficit hyperactivity disorder and substance use disorder. Recent research indicates that the practice of meditation, as a mental training technique, may improve cognitive control. However, if and to what extent regular long-term meditation practice may enhance performance monitoring is currently unknown. The present study examined effects of meditation practice on behavioral and electrophysiological indices of performance monitoring. A group of meditators and an experience-matched active control group (non-meditator athletes) performed an Eriksen-Flanker task while their brain activity was recorded using electroencephalography (EEG). Behaviorally, meditators made significantly fewer errors than controls on incongruent trials. EEG analyses revealed a general increase in the amplitude of two brain potentials associated with performance monitoring—the error negativity (Ne) or error-related negativity (ERN) and correct-related negativity (CRN)—in meditators compared to controls. These findings, which are indicative of enhanced performance monitoring in meditators, corroborate the idea that meditation could be a recommendable practice to train and improve cognitive control, specifically performance monitoring

A layered Bi2Te3@PPy cathode for aqueous zinc ion batteries: Mechanism and application in printed flexible batteries

Low‐cost, safe, and environmental‐friendly rechargeable aqueous zinc‐ion batteries (ZIBs) are promising as next‐generation energy storage devices for wearable electronics among other applications. However, sluggish ionic transport kinetics and the unstable electrode structure during ionic insertion/extraction hampers their deployment. Herein,  we propose a new cathode material based on a layered metal chalcogenide (LMC), bismuth telluride (Bi2Te3), coated with polypyrrole (PPy). Taking advantage of the PPy coating, the Bi2Te3@PPy composite presents strong ionic absorption affinity, high oxidation resistance, and high structural stability. The ZIBs based on Bi2Te3@PPy cathodes exhibit high capacities and ultra‐long lifespans of over 5000 cycles. They also present outstanding stability even under bending. In addition,  we analyze here the reaction mechanism using in situ X‐ray diffraction, X‐ray photoelectron spectroscopy, and computational tools and demonstrate that, in the aqueous system, Zn2+ is not inserted into the cathode as previously assumed. In contrast, proton charge storage dominates the process. Overall, this work not only shows the great potential of LMCs as ZIBs cathode materials and the advantages of PPy coating, but also clarifies the charge/discharge mechanism in rechargeable ZIBs based on LMCs